Intrathecal rosiglitazone acts at peroxisome proliferator-activated receptor-γ to rapidly inhibit neuropathic pain in rats
Intrathecal rosiglitazone acts at peroxisome proliferator-activated receptor-γ to rapidly inhibit neuropathic pain in rats
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DOI：
10.1016/j.jpain.2008.02.002
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发表时间：
2008-07-01
期刊：
影响因子：
4
通讯作者：
Taylor, Bradley K.
中科院分区：
文献类型：
--
作者：
Churi, Sajay B.;Abdel-Aleem, Omar S.;Taylor, Bradley K.
在这份报告中，我们证明了转录，表达和DNA结合特性的过氧化物酶体增殖物激活受体（PPAR）-γ亚型的过氧化物酶体增殖物激活核受体家族的脊髓与实时PCR，蛋白质印迹，电泳迁移率变动分析。为了检验脊髓PPAR-gamma的激活降低神经损伤诱导的异常性疼痛的假设，我们在坐骨神经的胫支和腓总支横断后在大鼠中鞘内施用PPAR-gamma激动剂和/或拮抗剂。单次注射天然（J2，15 d-PGJ 2中的15-脱氧-甘草酸）或合成（罗格列酮）PPAR-gamma激动剂剂量依赖性地降低机械和冷超敏反应。这些作用在100 μ g剂量下最大，在注射后60分钟达到峰值，这是一个快速的时间过程，表明作用机制不依赖于转录。同时给予PPAR-γ拮抗剂（双酚A二缩水甘油醚，BADGE）逆转了15 d-PGJ 2和罗格列酮的作用，进一步表明受体介导的作用。在没有神经损伤的动物中，罗格列酮没有改变运动协调、von Frey阈值或对冷刺激的退缩反应。腹膜内和脑室内注射PPAR-gamma激动剂（100 μ g）并没有降低机械和冷超敏反应，反对从鞘内空间扩散后的影响。我们的结论是，配体诱导的激活脊髓PPAR-gamma迅速逆转神经损伤引起的机械性异常性疼痛。新的或目前可用的药物针对脊髓的PPAR-gamma可能会产生重要的治疗效果的管理neuropathic pain.Perspective：PPAR-gamma受体激动剂，如罗格列酮和吡格列酮被批准为胰岛素增敏剂由美国食品和药物管理局。我们证明了PPAR-gamma在脊髓中的表达，并报告这些受体的激活抑制异常性疼痛。BBB-渗透性PPAR-gamma激动剂可能对神经性疼痛的管理产生重要的治疗效果。(C)2008年，美国疼痛协会。
In this report, we demonstrate the transcription, expression, and DNA-binding properties of the peroxisome proliferator-activated receptor (PPAR)-gamma subtype of the peroxisome proliferator-activated nuclear receptor family to the spinal cord with real-time PCR, Western blot, and electrophoretic mobility shift assay. To test the hypothesis that activation of spinal PPAR-gamma decreases nerve injury-induced allodynia, we intrathecally administered PPAR-gamma agonists and/or antagonists in rats after transection of the tibial and common peroneal branches of the sciatic nerve. Single injection of either a natural (15-deoxy-prostagland in J2, 15d-PGJ2) or synthetic (rosiglitazone) PPAR-gamma agonist dose-dependently decreased mechanical and cold hypersensitivity. These effects were maximal at a dose of 100 mu g and peaked at similar to 60 minutes after injection, a rapid time course suggestive of transcription-independent mechanisms of action. Concurrent administration of a PPAR-gamma antagonist (bisphenol A diglycidyl ether, BADGE) reversed the effects of 15d-PGJ2 and rosiglitazone, further indicating a receptor-mediated effect. In animals without nerve injury, rosiglitazone did not alter motor coordination, von Frey threshold, or withdrawal response to a cool stimulus. Intraperitoneal and intracerebroventricular administration of PPAR-gamma agonists (100 mu g) did not decrease mechanical and cold hypersensitivity, arguing against effects subsequent to diffusion from the intrathecal space. We conclude that ligand-induced activation of spinal PPAR-gamma rapidly reverses nerve injury-induced mechanical allodynia. New or currently available drugs targeted at spinal PPAR-gamma may yield important therapeutic effects for the management of neuropathic pain.Perspective: PPAR-gamma receptor agonists such as rosiglitazone and pioglitazone are approved as insulin sensitizers by the United States Food and Drug Administration. We demonstrate PPAR-gamma expression in the spinal cord and report that activation of these receptors inhibits allodynia. BBB-permeant PPAR-gamma agonists may yield important therapeutic effects for the management of neuropathic pain. (C) 2008 by the American Pain Society.